This program will investigate the cellular and molecular regulation of small and large intestinal motility. Significant progress was made during previous funding periods of this program in determining the cellular and molecular components of the neuromuscular apparatus of GI smooth muscles. The program is highly integrated with strong collaborations between participants, and a prolific track-record of publications in neurogastroenterology. We propose 5 projects for the next funding period. Project 1 will investigate the ionic mechanism of electrical rhythmicity in interstitial cells of Cajal (ICC). Specifically the ionic conductance responsible for pacemaker current will be characterized, and we will attempt to determine the molecular entity responsible for pacemaker currents. We will also investigate the Ca 2+ conductance responsible for entrainment of pacemakers in networks of ICC and propagation of electrical activity. Project 2 will investigate some of the specific post-junctional targets of inhibitory neurotransmission in GI muscles. Project 3 will investigate the molecular basis for and physiological function of stretch activated K+ channels. These channels stabilize membrane potential during muscle distension and mediate responses to nitrergic stimulation. Project 4 will investigate the neural circuitry responsible for migrating myoelectrical complexes in GI organs. These are periodic bursts of activity that clear the bowel of undigested contents and guard against bacterial overgrowth. Project 5 will investigate the development and plasticity of ICC. Many human motility disorders have been associated with loss of ICC, and it is important to understand the factors regulating development of ICC and causing loss of ICC in pathophysiological models. The 5 projects of the PPG will be supported by 3 Core facilities. Core A will be an administrative core that will arrange PPG meetings, maintain personnel records, assist with purchasing and travel, and help with grant reporting. Core B is a tissue, cell and cell culture facility that will provide all animals, tissues, dispersed cells, cultured tissues and cells, sorted cells, etc. for the 5 projects. Core C will offer molecular biology and morphology services to PPG projects. The PPG has made important contributions to the field of neurogastroenterology and to the training of young scientists in this field. The next funding period will investigate exciting new hypotheses that may enhance our ability to design effective therapies for GI motility disorders.